Apparatus and method for delivering intraluminal therapy

ABSTRACT

A catheter and methods for luminal therapy are provided wherein a catheter has an outer balloon with a multiplicity of apertures for infusing one or more therapeutic agents into a vessel wall, an intermediate balloon having a multiplicity of apertures offset from the apertures of outer balloon to serve as a baffle that reduces jetting and promotes uniform distribution of therapeutic agent exiting through the outer balloon, and an impermeable inner balloon disposed within the intermediate balloon that enables the intermediate and outer balloons to be forced into engagement with the vessel wall to dilate the vessel and disrupt plaque lining the vessel wall and to also facilitate the uniform delivery of the therapeutic agent. The outer balloon may include protrusions that contact the vessel wall to disrupt the plaque, bumpers to reduce washout during infusion of therapeutic agents; the intermediate balloon may include a texture, ribs or protrusions on its outer surface to prevent adhesion to the outer balloon during dilation of the vessel; and the catheter may include a guide wire lumen sized to accept an energy delivery device to delivery energy that enhances uptake of the therapeutic agent or prolongs therapeutic effectiveness of the agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 61/752,902, filed Jan. 15, 2013, the entirecontents of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to the delivery of intraluminaltherapy, such as treatment of vascular lesions. In some preferredembodiments, apparatus and methods are provided for treating calcifiedlesions in peripheral vasculature to prevent arterial dissections,atheroembolizations, perforations and restenosis following anangioplasty and/or stent procedures.

BACKGROUND OF THE INVENTION

A need exists for simple and efficacious delivery of intraluminaltherapies. Such therapies range from delivery of anti-mitotic agents toreduce the restenosis following angioplasty, to delivery of angiogenicfactors, delivery of therapeutic agents to reduce intravascularthrombus, delivery of therapeutic agents to improve arterial compliancethrough the structural alteration of intimal and medial calcification,delivery of fluent cross-linkable materials that may be hardened in situto provide support for a vessel (e.g., as is described in U.S. Pat. No.5,749,915 to Slepian, the entire contents of which is incorporatedherein by reference), or to exclude or reduce the development of anascent vascular aneurysms. Previously-known methods and apparatustypically involve use of multiple catheters and devices to accomplishsuch treatments, which adds time, cost and complexity, increasedexposure to ionizing radiation and risk of morbidity to previously-knowntherapeutic procedures. It therefore would be advantageous to providemethods and apparatus that simplify such previously-known procedures,reduce time, cost and complexity, and improve acute procedural successand long-term patient outcomes.

Percutaneous transluminal angioplasty of coronary and peripheralarteries (PTCA and PTA, respectively) are widely accepted as therevascularization procedures of choice in patients with ischemiccardiovascular syndromes (i.e., chronic and acute coronary ischemicsyndromes and chronic limb ischemia, including claudication and criticallimb ischemia). However, use of these conventional percutaneoustreatments has an important limitation: restenosis—the exuberantproliferation of smooth muscle cells that grow to re-occlude the treatedvessel segment, causing the reoccurrence of symptoms and necessitatingpotential reintervention.

Various adjuncts to angioplasty seek to reduce restenosis; these includeatherectomy (e.g., extractional, rotational, orbital, laser), bare metaland bare nitinol stents and, more recently, drug eluting stents (DES).The latter technology has been demonstrated to significantly reducecoronary artery restenosis when compared to angioplasty or bare metalstents, however, its use requires chronic administration of adjunctpharmacotherapies to prevent subacute stent thrombosis, the sudden andlife threatening clotting of the stent. Unfortunately, not all patientstolerate these essential pharmacotherapies due to impaired tolerance,allergic reactions or contraindication to such drug use (i.e., historyof previous bleeding) and/or their associated expense.

In peripheral arteries, the use of bare nitinol stents have been shownto be superior to balloon angioplasty alone and has emerged as the“default” percutaneous strategy for the treatment of chronic limbischemic syndromes, particularly in complex disease patterns involvingthe femoropopliteal artery. Despite their common use, nitinol stentspresent a substantial concern of in-stent restenosis (ISR), theproliferation of smooth muscle cells within the stent leading toocclusion of the stent lumen. ISR poses additional risk to the patientby necessitating additional vessel reintervention to re-establish vesselblood flow.

Currently, there is no established treatment for the vexing problem ofISR, which occurs in about 30%-50% of nitinol stents over a 1-2 yearfollow-up period, a rate that may increase depending on the patientdemographic (i.e., diabetics) and vessel morphology (small vesseldiameter, length of diseased vessel treated and the presence of vesselwall calcification). Importantly, there are presently no recognizedeffective and durable therapies to treat ISR; as such, emergingtechnologies focus on preventing restenosis through the application ofanti-restenotic therapeutic agents into the diseased vessel wall layersvia the vessel's luminal surface.

Anti-proliferative drugs (i.e., paclitaxel, sirolimus) retard smoothmuscle migration into an area of angioplasty-induced vessel injury andreduce restenosis. Drug delivery catheters have been designed tofacilitate the delivery of such therapeutic agents into the vessel wallvia its luminal surface. For example, U.S. Pat. No. 5,112,305 to Barathet al. describes a catheter having a single balloon including amultiplicity of protrusions. The protrusions include apertures thatenable a drug to be introduced into the balloon and infused through theapertures into the vessel wall. U.S. Pat. No. 5,049,132 to Shaffer etal. and U.S. Pat. No. 6,733,474 to Kusleika each describe a catheterhaving an impermeable inner balloon and an outer balloon having poresthrough which a drug may be infused into the vessel wall. U.S. Pat. No.5,681,281 to Vigil et al. similarly shows a catheter having animpermeable inner balloon and an outer balloon having a multiplicity ofapertured protrusions for injecting a drug into a vessel wall. U.S. Pat.No. 5,213,576 to Abiuso et al. describes a catheter having nestedballoons with offset apertures, to reduce jetting and provide moreuniform distribution of a drug infused into a vessel through thecatheter.

All of the previously-known systems described in the foregoing patentshave had drawbacks that have prevented commercialization of thosedesigns. For example, catheters having a single apertured balloon, suchas described in the above patent to Shaffer et al., cannot provideuniform distribution of a drug or other material around thecircumference or along the axis of the vessel due to jetting through theapertures. Catheters with apertured protrusions, such as described inthe above patents to Barath et al. and Vigil et al, are difficult tomanufacture and are believed to be prone to having the apertures cloggedwith debris when the balloon is embedded into the plaque lining thevessel wall. Also, the use of excessively high pressures within theballoon to clear the apertured protrusions may lead to excessivelynon-uniform drug infusion and potential vessel dissection.

On the other hand, in a catheter such as described in Abiuso et al.,nested balloons having offset apertures cause the inner balloon to serveas a baffle that reduces jetting through the apertures in the outerballoon, thereby providing a much more uniform infusion through theouter balloon. However, as the Abiuso catheter lacks an innerimpermeable balloon to move the drug infusing layers into appositionwith the vessel wall, there is the potential for much of the drug to bewashed into systemic circulation during deployment of the nestedballoons. Moreover, because Abiuso lacks a dilatation balloon, it has noability to disrupt calcified plaque, and accordingly, must be used witha separate dilatation balloon requiring additional catheter exchanges,contrast and radiation exposure and vessel irritation.

Recent clinical data has identified a variety of atherosclerotic plaquemorphologies in coronary and peripheral vessels, which prevent theeffective penetration of drug therapies into the various vessel layers.Specifically, the presence of dense fibro-calcific and calcified intimaland medial plaques, are associated with peri-procedural failure (due tovessel recoil and/or vessel wall dissection) and subsequent restenosisas these plaques are effective barriers to the penetration and uptake oftherapeutic drugs delivered luminally. As such, the instructions for use(IFU) of many current approved devices and inclusion/exclusionangiographic criteria of on-going regulatory trial designs specificallyexclude patients from device treatment with angiographic evidence ofseverely calcified vessels. Given the large and growing patientpopulation with diabetes and chronic kidney disease and conditionsassociated with heavy vessel wall calcification, this represents asubstantial patient population in which emerging therapies may beineffective.

In view of the many drawbacks of previously-known systems and methods,it would be desirable to provide apparatus and methods that overcomesuch drawbacks. In particular, it would be desirable to provide devicessuitable for intraluminal therapies, such as intravascular drug infusionsystems and methods, which reduce the number of equipment exchangesneeded to both disrupt intravascular plaque and to infuse ananti-stenotic agent into a vessel wall to reduce occurrence ofrestenosis.

It further would be desirable to provide devices and methods suitablefor intraluminal therapies, such as intravascular drug infusion systemsand methods, that permit a clinician to dilate a vessel to disruptcalcified plaque and then to infuse an anti-mitotic agent into thevessel wall through the disrupted plaque.

It still further would be desirable to provide devices and methodssuitable for intraluminal therapies, such as intravascular drug infusionsystems and methods, wherein a balloon of the catheter may include amultiplicity of apertures, such that the apertures are resistant toclogging during use of the balloon to dilate the vessel and disrupt theplaque.

Previously known systems also describe the use of various energy sourcesto deliver energy to fluent material infused into a vessel to pave avessel or create an in situ stent. Such systems are described, forexample, in U.S. Pat. No. 5,662,712 to Pathak et al. and U.S. Pat. No.5,899,917 to Edwards et al. A drawback of these systems, however, isthat each forms a new mechanical structure disposed within the vesselthat is separate and distinct from the vessel wall. Because thearteries, and to a lesser extent, the veins, expand and contract duringeach cardiac cycle due to pressure pulsations, such attempts to form arigid mechanical support that is not integrated with the vessel wall areinherently problematic.

It therefore further would be desirable to use existing vasculaturestructure to enhance or perpetuate the anti-mitotic effect of drugsinfused via an intravascular route. In particular, it would be desirableto employ application of energy, e.g., such as ultraviolet (UV) lightenergy, monopolar or bipolar generated radiofrequency (RF) generatedheat, or focused or unfocused ultrasonic energy, to potentiate thedelivery and effectiveness of anti-mitotic agents when administered fromthe luminal surface into the media and adventitial layers in thepresence of vascular calcification.

SUMMARY OF THE INVENTION

In view of the aforementioned drawbacks of previously-known systems andmethods, the present invention provides apparatus and methods thatreduce the number of equipment exchanges needed to both disruptintravascular plaque and to infuse therapeutic agents, such asanti-proliferative drugs or regenerative therapy agents, into a vesselwall to reduce occurrence of restenosis and/or promote angiogenesis, orto exclude a weakened vessel portion or reduce enlargement of a nascentaneurysm.

The present invention further provides devices and methods suitable forintraluminal therapies, such as intravascular drug infusion systems andmethods, that permit a clinician to dilate a vessel to disrupt calcifiedplaque and then to infuse therapeutic agents into the vessel wallthrough the disrupted plaque without the need to exchange catheters.

In accordance with another aspect of the present invention, a ballooncatheter is provided including an outer balloon having a multiplicity ofapertures for infusing one or more therapeutic agents into the vesselwall, an intermediate balloon having a multiplicity of apertures offsetfrom the apertures of outer balloon to serve as a baffle that reducesjetting and promotes uniform distribution of therapeutic agents throughthe outer balloon, and an impermeable inner balloon disposed within theintermediate balloon that enables the intermediate and outer balloons tobe forced into engagement with the vessel wall to dilate the vessel anddisrupt plaque lining the vessel wall.

The intermediate balloon optionally may include a texture, ribs orprotrusions on its outer surface that contacts the inner surface of theouter balloon to prevent the intermediate and outer balloons fromadhering to one another during dilation of the vessel. Such a featureensures that an annular space is maintained between the intermediate andouter balloons to facilitate uniform distribution of therapeutic agentsduring use of the catheter to perform therapy.

The outer balloon also may include bumpers at its proximal and distalends to facilitate delivery of therapeutic agents. The outer balloonoptionally may include a multiplicity of protrusions and apertures, suchthat the apertures are interposed between the protrusions so as toreduce the risk that the apertures become clogged during use of theballoon to dilate the vessel and disrupt the plaque.

In accordance with yet another aspect of the present invention, acatheter of the present invention is constructed to include a centrallumen that accommodates not only a conventional guide wire forpositioning the catheter, but also permits a wire carrying an energysource, such as an ultraviolet light source (“UV”), ultrasoundtransducer, electrically-powered resistive heater, or monopolar orbipolar radiofrequency (RF) heating element, to be substituted for theguide wire to deliver energy to the vessel wall segment where thetherapeutic agent was infused. In a preferred embodiment, the materialcomprising the distal end region of the catheter shaft, and preferablyalso the materials comprising the inner, intermediate and outerballoons, are selected to reduce absorption energy delivered to thematerial infused into the vessel wall.

Methods of using the apparatus of the present invention also areprovided, wherein the inventive catheter is first used, by inflating theinner balloon with a conventional balloon inflation system, to dilate avessel and disrupt calcified plaque disposed on the luminal lining. Theinner balloon is then depressurized, and one or more suitable fluenttherapeutic agents are infused into a space between the inner balloonand the intermediate balloon. The therapeutic agent passes through themultiplicity of apertures, designed of specific variable diameters andpositioned in specific patterns along the inner-most and outer-mostballoons, into the annular space between the intermediate and outerballoons, and then through the apertures in the outer balloon touniformly contact the disrupted plaque. Immediately, or after apredetermined interval, an energy delivery source, (e.g., a wiredelivering a UV light source, ultrasound transducer or resistiveheater), may be exchanged for the guide wire in the central lumen of thecatheter. The energy source is activated to enhance uptake of thetherapeutic agent through plaque, intima, media of the vessel wall sothat the therapeutic agent becomes deposited in the media, adventitiaand/or vaso vasorum of the vessel wall, or to activate a property of thefluent material to cause it to harden or otherwise transition toeffectuate a therapeutic or diagnostic purpose.

In accordance with one aspect of the present invention, the applicationof energy from the energy source to the therapeutic agent infused intothe vessel wall causes the agent to polymerize in the adventitia or vasovasorum, thereby reducing washout of the drug caused by circulationthrough the vaso vasorum. In this manner, the therapeutic agent will belocalized within the vessel wall, and serve as a reservoir that prolongsthe therapeutic effect of the agent, for example, by reducing occurrenceof late-term restenosis of the vessel. Alternatively, the agent maypolymerize to form a durable rigid or semi-rigid support within thevessel wall, that serves as an in situ stent that reduces reduction(restenosis) or enlargement (growth of an aneurysm) of the vesseldiameter, as suited for a particular therapy. Alternatively, energy fromthe energy source may be delivered to the vessel media, adventitiaand/or vaso vasorum prior to the application of the therapeutic agent orsubstance.

The apparatus and methods of the present invention therefore facilitateease of use by reducing the number of catheters required for theeffective pre-dilatation of a diseased vessel segment and facilitatesthe penetration and controlled, uniform delivery of one or moretherapeutic agents into the vessel layers using a baffled balloon, whichmay include a multiplicity of bumpers or protrusions configured todisrupt calcified plaque while avoiding clogging of the infusionapertures. Finally, the catheter provides a central lumen dimensioned toaccept an externally powered energy source, and the distal region of thecatheter preferably comprises materials that facilitate transmission ofsuch energy to the therapeutic agent while reducing absorption by thecatheter materials.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features of the invention, its nature and various advantageswill be apparent from the accompanying drawings and the followingdetailed description of the preferred embodiments, in which:

FIG. 1 is a plan view of the illustrative catheter constructed inaccordance with the principles of the present invention.

FIGS. 2A and 2B are, respectively, detailed plan and sectional views ofthe distal region of the catheter of FIG. 1.

FIGS. 3A and 3B are, respectively, detailed plan and sectional views ofthe distal region of an alternative catheter constructed in accordancewith the principles of the present invention.

FIGS. 4A and 4B are, respectively, detailed plan and sectional views ofthe distal region of another alternative catheter constructed inaccordance with the principles of the present invention.

FIGS. 5A to 5C illustrate steps of the using the catheter of FIG. 1 todilate a plaque-lined vessel and to infuse an anti-mitotic or othertherapeutic agent or drug.

FIG. 6 is a detailed sectional view of the balloons described in FIG. 5.

FIG. 7 is a detailed sectional view corresponding to encircled region 7in FIG. 5B.

FIG. 8 is a detailed sectional view corresponding to encircled region 8in FIG. 5C.

FIG. 9 illustrates a step of inserting an energy delivery wire into thecentral lumen of the catheter of the present invention during or afterthe step illustrated in FIG. 5C.

FIGS. 10A and 10B are, respectively, plan and sectional views of analternative embodiment of the catheter of the present invention.

FIG. 11 is a detailed sectional view corresponding to encircled region11 in FIG. 10B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring to FIG. 1, balloon catheter 20 constructed in accordance withthe principles of the present invention is described. Catheter 20includes proximal end 21, distal region 22 and elongated shaft 23.Proximal end 21, which is manipulated by the clinician, preferablyincludes hemostatic port 24 that permits conventional guide wire 25 tobe extended through a lumen of catheter 20, balloon inflation port 26and infusion agent port 27. Catheter preferably has a length anddiameter suitable for use in the desired cardiac or peripheral vessel,e.g., 130 to 150 cm in length with a diameter of 2.5 mm to 60 mm, in thecase of an abdominal aortic or thoracic aneurysm and balloon lengthsfrom 2 cm to 20 cm. Ports 24, 26 and 27 are conventional elements, andtogether with proximal end 21 of catheter 20 may comprise materialsconventionally used in the construction of intravascular catheters,e.g., polyethylene or polyterephthalate. Although catheter 20 isdepicted as an over-the-wire (“OTW”) catheter, it is to be understoodthat the inventive aspects of the catheter of the present inventionreadily may be employed in a rapid exchange (“RX”) catheter or in acatheter having a working lumen and an auxiliary lumen for guidewireinsertion such as that described in U.S. Pat. No. 7,018,358 toJoergensen, the entire contents of which is incorporated herein byreference.

Referring now to FIGS. 2A and 2B, distal region 22 of one embodiment ofcatheter 20 of the present invention is described. FIG. 2A depicts theexterior of distal region 22 with outer balloon 30 in an expanded statesuitable for dilating a vessel, while for purposes of clarity, FIG. 2Bdepicts a sectional view of the inner components of distal region 22with intermediate balloon 31 and inner balloon 32 in partially expandedstates suitable for infusing a therapeutic agent into a vessel wall.Outer balloon 30 preferably comprises a noncompliant or semi-compliantmaterial such as polyethylene or polyterephthalate. Outer balloon 30 issized and shape for insertion as appropriate for the intended therapyand bodily lumen. For example, outer balloon 30 may have a diameter inan expanded state of about 2.5-4.0 mm for insertion in smaller lumens,such as coronary vessels, about 4-7 mm for insertion in larger lumenssuch as peripheral vessels, or as much as 4-6 cm if the catheter isdesigned for use in providing therapy in the thoracic or abdominalaorta. Intermediate balloon 31 and inner balloon 32 preferably comprisea semi-compliant or compliant material such as polyterephthalate ornylon. As described in further detail below, in a preferred embodiment,inner balloon 32 is configured to expand intermediate balloon 31 andouter balloon 30 until outer balloon 30 reaches its maximum designeddiameter. In an alternative embodiment, outer balloon 30 also maycomprise a compliant material, while intermediate balloon 31 and innerballoon 32 also may comprise a non-compliant material.

Still referring to FIGS. 2A and 2B, outer balloon 30 has exteriorsurface 34 and multiplicity of through-wall apertures 35. In theembodiment depicted in FIG. 2A, apertures 35 illustratively are arrangedin a pattern where each row is offset by a predetermined angle, e.g.,about 45°, from an adjacent row; however, other patterns will readilyoccur to a person of ordinary skill in the design of balloon catheters.For example, each row or pattern of apertures on the outer balloon maybe aligned uniformly with adjacent rows; there may be a single row ofapertures on the outer balloon; there may be two rows of apertures onopposite sides of the outer balloon, etc. In addition, apertures 35 aredepicted as being circular in shape which may vary in diameter along thelength of the balloon, but could have any other desired shapes, such asrectangular, triangular or elliptical. Outer balloon 30, intermediateballoon 31 and inner balloon 32 preferably are affixed to catheter shaft23 at shoulders 36 and 37 via thermal bonds or glue welds.

As best shown in FIG. 2B, intermediate balloon 31 includes multiplicityof through-wall apertures 38 which may have varying diameters along theballoon length, and which preferably are offset from apertures 35 inouter balloon 30. In this manner, a fluent therapeutic agent introducedinto annular space 39 between the exterior of inner balloon 32 andinterior surface of intermediate balloon 31 will pass into annular space40 between the exterior of intermediate balloon 31 and the interiorsurface of outer balloon 30 without directly exiting through apertures35 in the outer balloon. Accordingly, when a therapeutic agent isintroduced into annular space 39 via infusion lumen 41 and infusion port27 on proximal end 21 (see FIG. 1), the agent passes from annular space39 to annular space 40, from which it uniformly exits outer balloon 30via apertures 35. Inflation port 26 on proximal end 21 (see FIG. 1) iscoupled to interior space 42 of inner balloon 32 via inflation lumen 43that extends through catheter shaft 23. Apertures 35 may be the samesize or a different size than apertures 38. Preferably, apertures 35 and38 are laser drilled and have a diameter between about 5 μm and about 50μm. In one embodiment, apertures 35 have a diameter of about 5 μm andapertures 38 have a diameter of about 10 μm. In addition, a subset ofthe multiplicity of apertures 35 or 38 may be differently sized fromanother subset of the multiplicity. For example, a distal portion of arow of apertures 35 each may have a first diameter and a proximalportion of the row each may have a second diameter, different from thefirst. In one embodiment, in a row of sixteen apertures, eight distalapertures each has a diameter of about 15-25 μm and eight proximalapertures each has a diameter of about 7-17 μm.

As depicted in FIG. 2B, after use of catheter 20 for dilating the vesselwall, inner balloon 32 may be inflated to any lower desired pressure toreduce the volume of therapeutic agent delivered into annular space 39and to facilitate the rate of delivery to the vessel wall.Alternatively, inner balloon 32 may be deflated entirely after thevessel dilatation step.

Still referring to FIG. 2B, catheter shaft 23 includes lumen 44,preferably centrally located in catheter shaft 23, to permit guide wire25 to be extended through catheter 20 to facilitate positioning ofdistal region 22 at a desired location in a patient's vasculature ororgan. Distal region 22 also may include radiopaque markers disposedalong catheter shaft 23, for example, in the vicinity of shoulders 36and 37, to facilitate positioning of the catheter under fluoroscopicimaging. In accordance with one aspect of the present invention, lumen44 preferably is sized to permit a wire containing an energy source,e.g., an ultraviolet light source (or light fiber), ultrasoundtransducer, or resistive heater, to be advanced into distal region 22 todeposit energy into the therapeutic agent or drug, to facilitate uptakeby the vessel wall or provide another therapeutic effect, as describedherein below. For such embodiments, balloons 30-31 and catheter shaft 23preferably comprise materials that permit light energy of selectedfrequencies to pass through the catheter without significant absorptionor loss of energy.

Referring now to FIGS. 3A and 3B, distal region 22′ of an alternativeballoon catheter is constructed similarly to distal region 22 of FIGS.2A and 2B, wherein like components are identified by like-primedreference numbers. Thus, for example, apertures 35′ in FIGS. 3A and 3Bcorrespond to apertures 35 of FIGS. 2A and 2B, etc. As will be observedby comparing FIGS. 2A, 2B and 3A, 3B, outer balloon 30′ includesproximal bumper 45 around the circumference of its proximal end anddistal bumper 46 around the circumference of its distal end, andapertures 35′ are aligned in uniform rows. Bumpers 45, 46 extend fromexterior surface 34′ so as to create a pocket between bumpers 45 and 46and between exterior surface 34′ and the luminal surface when bumpers45, 46 are urged into contact with the luminal surface. In this manner,bumpers 45, 46 facilitate delivery of therapeutic agents to the luminalsurface via the pocket such that the agents are delivered uniformlyalong the length of the balloon, reduce clogging of the apertures whenthe bumpers are urged into contact with the luminal surface, and reducethe risk that fluent material delivered to the vessel surface will bewashed into systemic circulation.

Referring now to FIGS. 4A and 4B, distal region 22″ of yet anotheralternative balloon catheter is constructed similarly to distal region22 of FIGS. 2A and 2B except that outer balloon 30″ further includesmultiplicity of solid protrusions 47 extending from exterior surface 34″and interposed between multiplicity of through-wall apertures 35″. Inthe embodiment depicted in FIG. 4A, protrusions 47 and apertures 35″illustratively are arranged in a regular pattern; however, otherpatterns will readily occur to a person of ordinary skill in the designof balloon catheters. Preferably, apertures 35″ are offset fromprotrusions 47 so as to reduce clogging of the apertures when theprotrusions are urged into contact with the luminal surface. Inaddition, while protrusions 47 are illustratively depicted assubstantially circular cylinders having rounded extremities, otherconfigurations, such as rectangular, conical or pyramidal structuresalso could be used. Protrusions 47 extend from exterior surface 34″ soas to create a pocket between exterior surface 34″ and the luminalsurface when protrusions 47 are urged into contact with the luminalsurface. In this manner, protrusions 47 facilitate delivery oftherapeutic agents to the luminal surface via the pocket, and reduce therisk that fluent material delivered to the vessel surface will be washedinto systemic circulation.

Referring now to FIGS. 5A to 5C, a method of using the catheter of FIGS.1 and 2 to perform an interventional procedure is described. As will bereadily understood to one of ordinary skill in the art, while the methodis described for use with the catheter of FIGS. 1 and 2, the alternativecatheters of FIGS. 3 and 4 may be used in a similar manner to thatdescribed below.

In FIG. 5A, guide wire 25 is placed in the vessel at the location of alesion or plaque P, or nascent aneurysm, as determined usingfluoroscopic imaging, contrast agents and conventional interventionaltechniques. Catheter 20 then is backloaded onto guide wire 25 byinserting the proximal end of the guide wire into the distal opening oflumen 44. Catheter 20 is advanced through the patient's vasculatureuntil distal region 22 is disposed in the region of interest, asdetermined using radiopaque markers on catheter shaft 23 andfluoroscopic imaging. When so disposed in patient's vessel V, distal end22 of catheter 20 will appear as depicted in FIG. 5A. In embodimentsprotrusions (FIG. 4), during manufacture of the catheter, outer balloon30′ or 30″ of the catheter may be wrapped or folded so that protrusions47 are substantially flush with the remainder of the balloon material,thus preventing the protrusions from snagging or abrading the vesselintima during advancement along guide wire 25 to the location ofinterest. Alternatively, a delivery sheath (not shown) may be disposedover distal region 22, 22′, or 22″ of the catheter to present a smoothouter surface for the catheter, and the sheath then may be retractedproximally to expose the distal region once it is at the desiredlocation in vessel V.

Referring now to FIGS. 5B, 6, and 7, a conventional inflator is coupledto inflation port 26 and an inflation medium, such as saline or a salinediluted iodinated contrast agent, is delivered via inflation lumen 43 toinner balloon 32 to cause inner balloon 32 to expand intermediateballoon 31 and outer balloon 30. As shown in FIG. 6, inner balloon 32may expand intermediate balloon 31 and outer balloon 30 so that pocket48 is created between outer balloon 30 and plaque P. In such anembodiment, pocket 48 may extend between bumpers 45 and 46 (FIG. 3) orprotrusions 47 (FIG. 4) contact plaque P and the intima of the vessel Vto dilate the vessel V and crack or disrupt plaque P. In addition, asshown in FIG. 7, inner balloon 32 may expand intermediate balloon 31 andouter balloon 30 into contact with plaque P and the intima of vessel Vto dilate the vessel V and disrupt or cause cracks C in the plaque P. Asinner balloon 32 expands, it contacts intermediate balloon 31 whichcontacts outer balloon 30 and causes outer balloon 30 to contact andcrack or disrupt plaque P.

In embodiments where the outer balloon includes protrusions (FIG. 4),the protrusions engage plaque at discrete locations and place the plaquein tension, causing it to fracture. One or more therapeutic agents areinfused through apertures 35, 35′, 35″ in outer balloon 30, 30′, 30″ andcontacts the plaque along fracture zones that enable the therapeuticagent to be rapidly taken up by the vessel intima. Because apertures 35″are interposed between the protrusions instead of extending through theprotrusions as in prior art systems, compressed plaque at the point ofcontact of the protrusions is expected not to clog the apertures. It isexpected that the foregoing arrangement of solid protrusions andinterposed apertures will enable better uptake of therapeutic agents incalcified lesions than has heretofore been achieved.

Referring to FIGS. 6 and 7, it is observed that vessel V comprises threelayers: intima I, medial M, and adventitial A, which is supplied by vasovasorum VV. It is known that the vaso vasorum VV supplies nourishment tovessel V and removes metabolic byproducts resulting from activity of thecells making up the vessel wall. In accordance with one aspect of thepresent invention, a therapeutic agent is infused into the wall of avessel V, and preferably into the adventitia A and/or vaso vasorum VV,while also locally reducing flow in the vaso vasorum VV to reducewashout of the therapeutic agent from the adventitia A and vaso vasorumVV. In this manner, the vessel wall serves as a reservoir for thetherapeutic agent, so that the infused therapeutic agent or drug isreleased from the adventitia A back into the medial M and intimalportions I of the vessel wall over a period of months to years, therebyprolonging the therapeutic effect of the infused agent or drug.

The foregoing benefits may be achieved by a number of modes. In oneembodiment, the therapeutic agent or drug may be designed so that whenactivated by supply of energy, e.g., irradiated by ultraviolet light,insonicated with ultrasound energy of a desired frequency, or heated bya resistive or other type of heater, the drug transitions from a fluentform to a gel-like or solid form. In this case, the therapeutic agentwill assist in blocking or reducing flow through the vaso vasorum, andreduce the rate at which the therapeutic agent or drug is removed fromthe selected portion of the vessel wall. Alternatively or in addition,if the therapeutic agent transforms to a gel-like or solid form, it willbe less susceptible to erosion. In an alternative embodiment, thedeposited energy may cause a component of the therapeutic agent to heatup to cause polymerization or cross-linking of fluent bioactivematerials and/or remodel or partially necrose portions of the adventitiaor vaso vasorum, thereby locally blocking or reducing flow through thevaso vasorum and producing a reservoir of the therapeutic agent thatprovides prolonged release. As a further alternative embodiment, thedeposited energy may function to enhance uptake of the therapeutic agentthrough the layers of the vessel wall. As a still further alternativeembodiment, the energy may directly cause partial remodeling or necrosisof the adventitia and/or vaso vasorum to produce the reservoir effectnoted above.

Referring now to FIGS. 5C and 8, after inner balloon 32 has beenexpanded to drive intermediate balloon 31, and outer balloon 30 (and, ifpresent, optional bumpers or protrusions) into contact with the vesselwall, inner balloon 32 is partially or completely deflated. Next, a vialor syringe containing a desired fluent therapeutic agent or drug, (e.g.,an anti-mitotic drug such as paclitaxel or sirolimus, angiogenic vector,or stem cells), is coupled to infusion port 27 on proximal end 21 andactivated to inject the agent through infusion lumen 41 into annularspace 39 between inner balloon 32 and intermediate balloon 31 (see FIG.2B). As indicated by the arrows in FIG. 5C, the agent passes throughapertures 38 in intermediate balloon 31 and into annular space 40between intermediate balloon 31 and outer balloon 30. Inner balloon 32may be partially or completely reinflated to cause the therapeutic agentto pass through apertures 38 and into annular space 40 betweenintermediate balloon 31 and outer balloon 30 before exiting throughapertures 35. Because apertures 38 are offset from apertures 35 in outerballoon 30, the agent circulates within annular space 40 before passingthrough apertures 35 and exiting outer balloon 30. Additionally, becauseagent moves laterally towards apertures 35, it will be more uniformlydistributed around the circumference and along the axial length of thevessel than previously-known single balloon systems. This bafflingeffect provided by intermediate balloon 31 is expected to reduce jettingof therapeutic agent exiting through apertures 35 of outer balloon 30,thus reducing the potential for vessel dissection.

As depicted in further detail in FIG. 8, the therapeutic agent exitsouter balloon into pockets 48 formed between cracks C in plaque and/orbetween bumpers, if provided. The therapeutic agent exits apertures 35into pockets 48, where it is expected to gain ready access to the vesselintima through cracks and fractures formed in plaque P during thedilatation step illustrated in FIG. 5B.

As will be apparent to one of ordinary skill in interventionalprocedures, the rate of infusion of therapeutic agent can be adjusted byvarying the pressure at which the agent is supplied from the syringe orvial through infusion port 27, or alternatively by adjusting the degreeof inflation of inner balloon 32. By adjusting the latter, the cliniciancan reduce the volume of annular space 39, reducing the volume oftherapeutic agent that must be used during the procedure. In addition,after infusing the therapeutic agent into annular space 39, theclinician may increase the pressure in inner balloon 32 to pressurizeannular spaces 39 and 40 and enhance the rate at which therapeutic agentexits apertures 35 and is infused into the vessel wall. Therapeuticagent deposited in pockets 48 preferably is taken up by the cells in thevarious layers of the wall of vessel V by normal cellular processes, asopposed to traumatically (e.g., by cleaving intercellular connections).

In addition, as will be readily understood to one of ordinary skill inthe art, while the balloon catheter is generally described as deliveringa therapeutic agent, such as an anti-mitotic drug, to plaque, thedisclosure is not limited thereto. The therapeutic agent may be selectedto treat any condition where subintimal injection would be beneficial.For example, the therapeutic agent may be selected for treating anascent or existing aneurysm when the balloon catheter is deliveredproximate to an aneurysm. As another example, the therapeutic agent maybe selected to induce angiogenesis, delivered either transluminally orinto the sub-intimal space. The therapeutic agent may comprise, forexample, one or more regenerative agents, anti-inflammatory agents,anti-allergenic agents, anti-bacterial agents, anti-viral agents,anticholinergic agents, antihistamines, antithrombotic agents,anti-scarring agents, antiproliferative agents, antihypertensive agents,anti-restenosis agents, healing promoting agents, vitamins, proteins,genes, growth factors, cells, stem cells, vectors, RNA, or DNA.

FIG. 9 illustrates a final optional step in accordance with the methodof present invention for infusing one or more therapeutic agents intothe wall of vessel V. FIG. 9 is similar to FIG. 5C, except that in thisstep guide wire 25 is removed or retracted, and energy delivery device50 carrying an energy deposition element is advanced through lumen 44 ofcatheter 20 and disposed in distal region 22. The energy deliveryelement, located in the distal region of energy delivery device 50,preferably includes one or more radiopaque markers to indicatepositioning of the distal region under fluoroscopic imaging. Energydelivery device 50 preferably has a diameter between 0.018″ to 0.035″and may comprise an optical fiber or source for delivering ultravioletlight, ultrasonic energy, or heat. Such devices, and the energy sourcesthat are coupled to the proximal ends of such devices, are known in theart and accordingly are not described in detail here. Of particularimportance, however, if a UV light or ultrasonic energy delivery device50 is employed, catheter 20 preferably is constructed so that asubstantial part of the energy is delivered to the vessel wall withoutbeing absorbed by the catheter material, and the energy absorbed by thevessel wall has some therapeutic benefit, e.g., activates thetherapeutic agent. Energy emitted by energy delivery device 50 andabsorbed by vessel V is represented by the solid arrows in FIG. 9.

As discussed above with respect to FIGS. 6 and 7, energy delivery device50 may provide a therapeutic effect either by facilitating uptake of thetherapeutic agent by the vessel wall; by activating the therapeuticagent; by heating the therapeutic agent to effect a change to the vesselwall structure; or by directing delivering energy to selected layers ofthe vessel wall to cause polymerization or cross-linking of fluenttherapeutic agents (e.g., as described in U.S. Pat. No. 5,749,915 toSlepian localized necrosis or remodeling of collagen contained withinthe vessel wall.

In one embodiment, the deposited energy enhances uptake of thetherapeutic agent through the layers of the vessel wall, for example, byactivating moieties bound to the effective portion (e.g.,anti-proliferative portion) of the therapeutic agent, (e.g., asdescribed in U.S. Pat. No. 4,590,211 to Vorhees). Alternatively, thetherapeutic agent or drug may be designed so that when irradiated byultraviolet light, or insonicated with ultrasound energy of a desiredfrequency, the drug transitions from a fluent form to a gel-like orsolid form. In this case, the therapeutic agent will assist in blockingor reducing flow through the vaso vasorum, and reduce the rate at whichthe therapeutic agent or drug is removed from the selected portion ofthe vessel wall. Alternatively or in addition, if the therapeutic agenttransforms to a gel-like or solid form, it will be less susceptible toerosion, thereby locally prolonging the therapeutic effect of the agent.

In a further alternative embodiment, the energy deposited by deliverydevice 50 may cause a component of the therapeutic agent to heat up andremodel collagen of, or partially necrose portions of, the adventitia orvaso vasorum. This effect also may cause a localized blockage that stopsor reduces flow through the vaso vasorum and act to produce a localizedreservoir of the therapeutic agent that provides prolonged release. Asyet another alternative embodiment, the UV or ultrasonic energy maydirectly cause partial remodeling or necrosis of the adventitia and/orvaso vasorum to create localized blockage of the vaso vasorum to producethe reservoir effect noted above.

Referring again to FIG. 9, energy delivery device 50 may be configuredto deliver energy to vessel V during and after, or alternatively only apredetermined interval after, the therapeutic agent is delivered bycatheter 20. Once the process of delivering the therapeutic agent intothe vessel wall is completed, and the appropriate amount of energy hasbeen delivered to enhance or prolong the therapeutic effect of thetherapeutic agent, energy delivery device 50 may be withdrawn. Next,suction may be drawn on infusion lumen 41 to remove any excesstherapeutic agent from annular spaces 39 and 40 to collapse intermediateballoon 31 and retract outer balloon 30 away from the vessel wall. In anembodiment where the outer balloon includes protrusions, the outerballoon may be constructed so that, when deflated, the balloonpreferentially will fold to enclose the protrusions and reduce the riskof abrading the vessel wall during removal. Alternatively, or inaddition, an open-ended sheath (not shown) may be advanced over theexterior surface of catheter shaft 23 and the exterior of outer balloon30 to facilitate removal of catheter 20. Once catheter 20 is removedfrom the patient's vasculature, the access site may be closed usingstandard interventional techniques.

Referring now to FIGS. 10A, 10B and 11, an alternative embodiment ofapparatus constructed in accordance with the principles of the presentinvention is described. Catheter 60 includes elongated catheter shaft 61having distal region 62 and outer balloon 63. The proximal end ofcatheter shaft 61 is similar in construction to catheter 20 andpreferably includes a hemostatic guide wire port, balloon inflation portand infusion port. As shown in FIG. 10B (which corresponds to aninflation state similar to FIG. 2B), distal region 62 includes outerballoon 63, intermediate balloon 64 and inner balloon 65. As forcatheter 20 of the preceding embodiment, inner balloon 65 is fluidimpermeable and is coupled via an inflation lumen to an inflation porton the proximal end. Likewise, intermediate balloon 64 includes amultiplicity of through-wall apertures 66 (see FIG. 11) and is coupledvia an infusion lumen to an infusion port disposed on the proximal endof the catheter. Outer balloon 63 includes one or more spiralprotrusions 67 and a multiplicity of through-wall apertures 68.

Catheter 60 differs from the embodiment of FIG. 1 in that the exteriorsurface of outer balloon 63 includes protrusions 67 arranged as a spiralridge. In addition, whereas intermediate balloon 64 of the embodiment ofFIG. 1 may contain a textured surface to ensure that intermediateballoon 64 does not adhere to outer balloon 63, intermediate balloon 64in the embodiment of FIGS. 10 and 11 includes a macroscopic feature toprevent such adhesion. In particular, intermediate balloon 64 includesspiral rib 69, preferably comprised of the same material and potentiallyintegrally formed with intermediate balloon 64, disposed on itsexterior-facing surface of the intermediate balloon. In this manner,spiral rib 69 contacts the inner surface of outer balloon to ensure thatannular space 70 is maintained between intermediate balloon 64 and outerballoon 63 when inner balloon 65 is inflated to urge intermediateballoon 64 and outer balloon 63 into contact with a vessel wall todilate the vessel and disrupt plaque.

While in the embodiment of FIGS. 10 and 11 protrusions 67 are configuredas a spiral ridge having a rounded extremity, it should be understoodthat other patterns will readily occur to a person of ordinary skill inthe design of balloon catheters, such as structures having rectangular,conical or pyramidal cross-sections, as may be desirable to fracturesevere calcifications. Similarly, while apertures 68 are depicted asbeing circular, they may have any other desired shape, such asrectangular, triangular or elliptical. Preferably, apertures 68 areoffset from protrusions 67 so as to reduce clogging of the apertureswhen the protrusions are urged into contact with the luminal surface.Likewise, apertures 66 in intermediate balloon 64 may be offset fromapertures 68 in outer balloon 63 to achieve the benefits describedabove.

Finally, although the macroscopic feature in intermediate balloon 64 isillustratively depicted as comprising spiral rib 69 having asubstantially circular cross-section, this feature could have othercross-sections, such as rectangular, elliptical or triangular. Inaddition, spiral rib 69 need not form a continuous structure, butinstead could comprise a multiplicity of discrete structures, similar inshape to protrusions 47 disposed on outer balloon 30″ of the embodimentof FIG. 4. For example, intermediate balloon 64 and outer balloon 63 maycomprise the same material having the same protrusions disposed on theirrespective exterior surfaces. In this manner, construction of the distalend of the catheter of the present invention could be simplified, solong as the apertures in the intermediate and outer balloons arestaggered or offset to provide the baffle action discussed above.

While preferred illustrative embodiments of the invention are describedabove, it will be apparent to one skilled in the art that variouschanges and modifications may be made therein without departing from theinvention. The appended claims are intended to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

What is claimed is:
 1. An apparatus for intraluminal therapy comprising:an elongated catheter shaft having a proximal end and a distal region,and an inflation lumen and infusion lumen extending from the proximalend to the distal region; a fluid impermeable balloon affixed to thedistal region, the fluid impermeable balloon having an exterior surface;an intermediate balloon affixed to the distal region to envelop thefluid impermeable balloon, the intermediate balloon having an interiorsurface and a first multiplicity of through-wall apertures; and an outerballoon affixed to the distal region to envelop the intermediateballoon, the outer balloon having an exterior surface and a secondmultiplicity of through-wall apertures offset from the firstmultiplicity of apertures, wherein the inflation lumen is coupled to afirst space enclosed by the fluid impermeable balloon, the infusionlumen is coupled to a second space defined by the exterior surface ofthe fluid impermeable balloon and the interior surface of theintermediate balloon, and a third space between the intermediate balloonand the outer balloon is accessible only through the first multiplicityof through-wall apertures, and wherein the fluid impermeable balloon isconfigured to contact and expand the intermediate balloon against theouter balloon, and to expand the outer balloon into contact with aluminal wall to dilate the luminal wall.
 2. The apparatus of claim 1,wherein the intermediate balloon and outer balloon are configured sothat fluid infused into the intermediate balloon passes through thefirst multiplicity of apertures and into the third space between theintermediate balloon and the outer balloon before exiting through thesecond multiplicity of apertures.
 3. The apparatus of claim 2, whereinthe intermediate balloon functions as a baffle that uniformlydistributes fluid infused into the intermediate balloon into the thirdspace between the intermediate balloon and the outer balloon.
 4. Theapparatus of claim 1, further comprising a multiplicity of protrusionsextending from the exterior surface of the outer balloon, wherein theouter balloon is adapted to expand such that the protrusions contact theluminal wall.
 5. The apparatus of claim 4, wherein individual aperturesin the second multiplicity of apertures are interposed betweenindividual protrusions in the multiplicity of protrusions.
 6. Theapparatus of claim 4, wherein at least some of the protrusions of themultiplicity of protrusions have a cylindrical, rectangular, conical orpyramidal shape.
 7. The apparatus of claim 4, wherein at least some ofthe protrusions of the multiplicity of protrusions are configured toform a spiral around a circumference of the outer balloon.
 8. Theapparatus of claim 1, further comprising: a proximal bumper extendingfrom the exterior surface of the outer balloon around a circumference ofa proximal end of the outer balloon, and a distal bumper extending fromthe exterior surface of the outer balloon around the circumference of adistal end of the outer balloon, wherein the proximal and distal bumpersare spaced apart and contact the vessel wall.
 9. The apparatus of claim1, wherein at least some of the apertures of the first or secondmultiplicity of apertures has a circular, rectangular, elliptical ortriangular shape.
 10. The apparatus of claim 1, wherein the cathetershaft further comprises a lumen sized to accept an energy deliverydevice.
 11. The apparatus of claim 10, wherein the energy deliverydevice is configured to supply ultraviolet irradiation, ultrasonicenergy or heat.
 12. The apparatus of claim 1, wherein the intermediateballoon and outer balloon are configured so that fluid infused into theintermediate balloon passes through the first multiplicity of aperturesand into the third s ace between the intermediate balloon and the outerballoon and moves laterally within the third space before exitingthrough the second multiplicity of apertures.
 13. The apparatus of claim10, wherein the catheter shaft in the distal region, the fluidimpermeable balloon, the intermediate balloon and the outer balloon eachcomprises a material selected to transmit ultraviolet radiation orultrasonic energy.
 14. The apparatus of claim 1, further comprising amultiplicity of protrusions disposed an exterior surface of theintermediate balloon to prevent adhesion of the intermediate balloon tothe outer balloon during dilatation of the vessel wall.